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Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J

Abstract

Membrane-bound phosphoinositides are signalling molecules that have a key role in vesicle trafficking in eukaryotic cells1. Proteins that bind specific phosphoinositides mediate interactions between membrane-bounded compartments whose identity is partially encoded by cytoplasmic phospholipid tags. Little is known about the localization and regulation of mammalian phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2), a phospholipid present in small quantities that regulates membrane trafficking in the endosome–lysosome axis in yeast2. Here we describe a multi-organ disorder with neuronal degeneration in the central nervous system, peripheral neuronopathy and diluted pigmentation in the ‘pale tremor’ mouse. Positional cloning identified insertion of ETn2β (early transposon 2β)3 into intron 18 of Fig4 (A530089I17Rik), the homologue of a yeast SAC (suppressor of actin) domain PtdIns(3,5)P2 5-phosphatase located in the vacuolar membrane. The abnormal concentration of PtdIns(3,5)P2 in cultured fibroblasts from pale tremor mice demonstrates the conserved biochemical function of mammalian Fig4. The cytoplasm of fibroblasts from pale tremor mice is filled with large vacuoles that are immunoreactive for LAMP-2 (lysosomal-associated membrane protein 2), consistent with dysfunction of the late endosome–lysosome axis. Neonatal neurodegeneration in sensory and autonomic ganglia is followed by loss of neurons from layers four and five of the cortex, deep cerebellar nuclei and other localized brain regions. The sciatic nerve exhibits reduced numbers of large-diameter myelinated axons, slowed nerve conduction velocity and reduced amplitude of compound muscle action potentials. We identified pathogenic mutations of human FIG4 (KIAA0274) on chromosome 6q21 in four unrelated patients with hereditary motor and sensory neuropathy. This novel form of autosomal recessive Charcot–Marie–Tooth disorder is designated CMT4J.

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Figure 1: Phenotypes of homozygous pale tremor mice.
Figure 2: Neuropathology in pale tremor mice.
Figure 3: Pathological abnormalities in peripheral nerves.
Figure 4: Mutations of FIG4 in patients with CMT disorder.
Figure 5: Yeast Fig4 Ile > Thr is defective in activation of kinase Fab1/PIKfyve.

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Acknowledgements

For discussions and advice we are grateful to A. Dlugosz, E. Feldman, D. Goldowitz, J. Hammond, L. Isom, J. M. Jones, A. Lieberman, M. Khajavi, J. Swanson, K. Verhey and S. H. Yang. S. Cheek and M. Hancock provided technical assistance. This research was supported by NIH research grants (M.H.M., L.W. and J.R.L.) and NIH predoctoral training (C.Y.C.).

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Correspondence to Miriam H. Meisler.

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Supplementary information

Supplementary Information 1

This file contains Supplementary Video Legend, Supplementary Figures 1-10 with Legends and Supplementary Discussion. (PDF 4003 kb)

Supplementary Information 2

This file contains Supplementary Video 1 which shows the typical movement disorder of the plt mouse. The mouse is four weeks old. (MOV 2031 kb)

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Chow, C., Zhang, Y., Dowling, J. et al. Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J. Nature 448, 68–72 (2007). https://doi.org/10.1038/nature05876

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